Abstract
New oral anticoagulants, including dabigatran, rivaroxaban, and apixaban, have been recently approved for primary and secondary prophylaxis of thromboembolic conditions. However, there is no clear strategy for managing and reversing their anticoagulant effects. We aimed to summarize the available evidence for clinical management and reversal of bleeding associated with new oral anticoagulants. Using a systematic review approach, we aimed to identify studies describing reversal strategies for dabigatran, rivaroxaban, and apixaban. The search was conducted using Medline, EMBASE, HealthSTAR, and grey literature. We included laboratory and human studies. We included 23 studies reported in 37 out of 106 potentially relevant references. Four studies were conducted in humans and the rest were in vitro and in vivo studies. The majority of the studies evaluated the use of prothrombinase complex concentrate (PCC), either activated or inactivated, and recombinant activated factor VII (rFVIIa). Other interventions were also identified. Laboratory studies suggest that hemostatic parameters and bleeding might be partially or completely corrected by PCC for rivaroxaban better than dabigatran. Studies in humans suggest that PCC might reverse the effects of rivaroxaban better than dabigatran assessed by hemostatic tests. We were not able to locate studies evaluating the clinical efficacy of these agents. The best available evidence suggests that PCC (activated or inactivated) might be the best option for reversing new anticoagulants. Evidence for rFVIIa is less compelling. There might be differences in the efficacy of reversing agents for different anticoagulants. Studies assessing the clinical efficacy of these reversal agents are urgently needed.
Highlights
Dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) are new oral anticoagulants (NOACs) that are approved in North America for reducing the risk of venous thromboembolism after hip or knee replacement and for stroke prevention in nonvalvular atrial fibrillation
In the case of warfarin, the management of bleeding is well known; experience in the management of bleeding complications associated with NOACs is very limited and there are no available antidotes
The first study included healthy volunteers to whom rivaroxaban (20 mg twice a day) or dabigatran (150 mg twice a day) was administered for 2.5 days, after which they received a single dose of 50 IU/kg of four-factor (II, VII, IX, X) prothrombinase complex concentrate (PCC), and its effects on prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), ecarin clotting time (ECT), and endogenous thrombin potential (ETP) were evaluated [26]
Summary
Dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) are new oral anticoagulants (NOACs) that are approved in North America for reducing the risk of venous thromboembolism after hip or knee replacement and for stroke prevention in nonvalvular atrial fibrillation. It has been noted that a normal thrombin time may indicate a lack of dabigatran activity, this test is extremely sensitive to very small amounts of the drug, rendering it unsuitable for clinical use Owing to their predictable pharmacokinetic and pharmacodynamic profiles, NOACs do not require routine laboratory monitoring, but this does not preclude the need to monitor specific coagulation-related conditions. The best evidence so far comes from four studies in healthy volunteers who were receiving NOACs. The first study included healthy volunteers to whom rivaroxaban (20 mg twice a day) or dabigatran (150 mg twice a day) was administered for 2.5 days, after which they received a single dose of 50 IU/kg of four-factor (II, VII, IX, X) PCC, and its effects on PT, aPTT, thrombin time (TT), ecarin clotting time (ECT), and endogenous thrombin potential (ETP) were evaluated [26]. When considering the use of these reversal agents, clinicians should very carefully consider the trade-off between benefits and potential risk
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